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The modern era of drug development for Alzheimer's disease began with the proposal of the cholinergic hypothesis of memory impairment and the 1984 research criteria for Alzheimer's disease. Since then, despite the evaluation of numerous potential treatments in clinical trials, only four cholinesterase inhibitors and memantine have shown sufficient safety and efficacy to allow marketing approval at an international level. Although this is probably because the other drugs tested were ineffective, inadequate clinical development methods have also been blamed for the failures. Here, we review the development of treatments for Alzheimer's disease during the past 30 years, considering the drugs, potential targets, late-stage clinical trials, development methods, emerging use of biomarkers and evolution of regulatory considerations in order to summarize advances and anticipate future developments. We have considered late-stage Alzheimer's disease drug development from 1984 to 2013, including individual clinical trials, systematic and qualitative reviews, meta-analyses, methods, commentaries, position papers and guidelines. We then review the evolution of drugs in late clinical development, methods, biomarkers and regulatory issues. Although a range of small molecules and biological products against many targets have been investigated in clinical trials, the predominant drug targets have been the cholinergic system and the amyloid cascade. Trial methods have evolved incrementally: inclusion criteria have largely remained focused on mild-to-moderate Alzheimer's disease criteria, recently extending to early or prodromal Alzheimer disease or 'mild cognitive impairment due to Alzheimer's disease', for drugs considered to be disease modifying. The duration of trials has remained at 6-12 months for drugs intended to improve symptoms; 18- to 24-month trials have been established for drugs expected to attenuate clinical course. Cognitive performance, activities of daily living, global change and severity ratings have persisted as the primary clinically relevant outcomes. Regulatory guidance and oversight have evolved to allow for enrichment of early-stage Alzheimer's disease trial samples using biomarkers and phase-specific outcomes. In conclusion, validated drug targets for Alzheimer's disease remain to be developed. Only drugs that affect an aspect of cholinergic function have shown consistent, but modest, clinical effects in late-phase trials. There is opportunity for substantial improvements in drug discovery and clinical development methods.

BackgroundIn Alzheimer's disease, there is a marked decline in the function of cholinergic neurons in the brain. However, studies of treatment with cholinesterase inhibitors have produced conflicting results. We conducted a multicenter trial to evaluate whether the cholinesterase inhibitor tacrine (1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydrate) could improve cognition in patients with Alzheimer's disease.MethodsOf 632 eligible patients with probable Alzheimer's disease, 215 improved while receiving tacrine during a preliminary crossover phase to determine responsiveness and the best dose. The 215 patients were randomly assigned to receive either placebo or their best dose of tacrine (10 or 20 mg four times a day) in a six-week, double-blind trial. The primary measures of efficacy were the cognitive subscale of the Alzheimer's Disease Assessment Scale and the Clinical Global Impression of Change scale; the secondary measures included the Mini-Mental State Examination and the assessment of the activities of daily living.ResultsAt the end of the six-week trial, the patients receiving tacrine had a mean adjusted cognitive-subscale score of 30.3 (Alzheimer's Disease Assessment Scale) as compared with 32.7 in patients receiving placebo. This represents a smaller decline (by 2.4 points) in cognitive performance in the tacrine group (P < 0.001). There were no differences between the groups in their global-rating scores. The tacrine group had a significantly smaller decline in the activities of daily living. The results of the Mini-Mental State Examination favored tacrine, but the differences were small and not statistically significant (a score of 16.0 with tacrine vs. 15.3 with placebo; P = 0.08). Gastrointestinal symptoms, elevation of aminotransferase levels, and headache were the most frequent side effects; all could be reversed by reducing the dose or discontinuing treatment.ConclusionsIn this short-term study in patients with Alzheimer's disease who were selected for apparent responsiveness to tacrine, treatment with tacrine resulted in a statistically significant reduction in the decline of cognitive function, although this reduction was not large enough to be detected by the study physicians' global assessments of the patients.

Context: Amyloid-beta peptide (Abeta(42)) has been implicated in the pathogenesis of Alzheimer disease (AD). Tarenflurbil, a selective Abeta(42)-lowering agent, demonstrated encouraging results on cognitive and functional outcomes among mildly affected patients in an earlier phase 2 trial.Objective: To determine the efficacy, safety, and tolerability of tarenflurbil.Design, Setting, and Patients: A multicenter, randomized, double-blind, placebo-controlled trial enrolling patients with mild AD was conducted at 133 trial sites in the United States between February 21, 2005, and April 30, 2008. Concomitant treatment with cholinesterase inhibitors or memantine was permitted.Intervention: Tarenflurbil, 800 mg, or placebo, administered twice a day.Main Outcome Measures: Co-primary efficacy end points were the change from baseline to month 18 in total score on the subscale of the Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog, 80-point version) and Alzheimer Disease Cooperative Studies-activities of daily living (ADCS-ADL) scale. Additional prespecified slope analyses explored the possibility of disease modification.Results: Of the 1684 participants randomized, 1649 were included in the analysis, and 1046 completed the trial. Tarenflurbil had no beneficial effect on the co-primary outcomes (difference in change from baseline to month 18 vs placebo, based on least squares means: 0.1 for ADAS-Cog; 95% CI, -0.9 to 1.1; P = .86 and -0.5 for ADCS-ADL; 95% CI, -1.9 to 0.9; P = .48) using an intent-to-treat analysis. No significant differences occurred in the secondary outcomes. The ADAS-Cog score decreased by 7.1 points over 18 months. The tarenflurbil group had a small increase in frequency of dizziness, anemia, and infections.Conclusion: Tarenflurbil did not slow cognitive decline or the loss of activities of daily living in patients with mild AD.Trial Registration: clinicaltrials.gov Identifier: NCT00105547. [ABSTRACT FROM AUTHOR]

Context: Blood levels of homocysteine may be increased in Alzheimer disease (AD) and hyperhomocysteinemia may contribute to disease pathophysiology by vascular and direct neurotoxic mechanisms. Even in the absence of vitamin deficiency, homocysteine levels can be reduced by administration of high-dose supplements of folic acid and vitamins B(6) and B(12). Prior studies of B vitamins to reduce homocysteine in AD have not had sufficient size or duration to assess their effect on cognitive decline.Objective: To determine the efficacy and safety of B vitamin supplementation in the treatment of AD.Design, Setting, and Patients: A multicenter, randomized, double-blind controlled clinical trial of high-dose folate, vitamin B(6), and vitamin B(12) supplementation in 409 (of 601 screened) individuals with mild to moderate AD (Mini-Mental State Examination scores between 14 and 26, inclusive) and normal folic acid, vitamin B(12), and homocysteine levels. The study was conducted between February 20, 2003, and December 15, 2006, at clinical research sites of the Alzheimer Disease Cooperative Study located throughout the United States.Intervention: Participants were randomly assigned to 2 groups of unequal size to increase enrollment (60% treated with high-dose supplements [5 mg/d of folate, 25 mg/d of vitamin B(6), 1 mg/d of vitamin B(12)] and 40% treated with identical placebo); duration of treatment was 18 months.Main Outcome Measure: Change in the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-cog).Results: A total of 340 participants (202 in active treatment group and 138 in placebo group) completed the trial while taking study medication. Although the vitamin supplement regimen was effective in reducing homocysteine levels (mean [SD], -2.42 [3.35] in active treatment group vs -0.86 [2.59] in placebo group; P < .001), it had no beneficial effect on the primary cognitive measure, rate of change in ADAS-cog score during 18 months (0.372 points per month for placebo group vs 0.401 points per month for active treatment group, P = .52; 95% confidence interval of rate difference, -0.06 to 0.12; based on the intention-to-treat generalized estimating equations model), or on any secondary measures. A higher quantity of adverse events involving depression was observed in the group treated with vitamin supplements.Conclusion: This regimen of high-dose B vitamin supplements does not slow cognitive decline in individuals with mild to moderate AD.Trial Registration: clinicaltrials.gov Identifier: NCT00056225. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Second-generation antidepressants are commonly used to treat major depression in late-life. This systematic review and meta-analysis was undertaken to assess the evidence for efficacy of second-generation antidepressants in late-life major depression. METHODS: The Cochrane Library (2006 [3]), MEDLINE (1966 to August 2006), and meeting presentations were searched for trials of second-generation antidepressants (nontricyclics) marketed in the United States. Published and unpublished placebo-controlled randomized clinical trials in outpatients 60 years and older, with nonpsychotic, unipolar major depression were selected. Clinical characteristics and outcomes were extracted. Outcomes were expressed as odds ratios (OR), risk differences, and weighted mean differences. RESULTS: Ten unique trials (four unpublished) with 13 contrasts met selection criteria. Trials were 6-12 weeks duration, and included 2,377 patients who received active drug and 1,788 received placebo. The ORs by meta-analysis for response and remission were 1.40 (95% confidence interval [CI] 1.24-1.57, z = 5.45, N = 13, p <0.001) and 1.27 (CI 1.12-1.44, z = 3.67, N = 13, p <0.001), respectively, with significant heterogeneity for response and remission among the trials. Mean pooled response rates for antidepressant and placebo were 44.4% and 34.7%, respectively. The OR for response was significantly higher in the 10-12 week trials (OR = 1.73, CI 1.42-2.09, z = 5.51, N = 5, p <0.001) than the 6-8 week trials (OR = 1.22, CI 1.05-1.42, z = 2.60, N = 8, p = 0.01). ORs for discontinuation for any reason and for adverse events were significantly higher with drugs than with placebo. CONCLUSIONS: Antidepressants are more effective than placebo in elderly depressed subjects although effects are modest and vary. Identification of the characteristics of responders and nonresponders will be crucial to improving treatment outcomes. [ABSTRACT FROM AUTHOR]

Objective: The study measured the effects of atypical antipsychotics on psychiatric and behavioral symptoms in patients with Alzheimer's disease and psychosis or agitated behavior.Method: The Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) Alzheimer's disease effectiveness study included 421 outpatients with Alzheimer's disease and psychosis or agitated/aggressive behavior. Patients were assigned randomly to masked, flexible-dose treatment with olanzapine, quetiapine, risperidone, or placebo for up to 36 weeks. Patients could be randomly reassigned to a different medication at the clinician's discretion, which ended phase 1. Psychiatric and behavioral symptoms, functioning, cognition, care needs, and quality of life were measured at regular intervals.Results: In relation to placebo, the last observation in phase 1 showed greater improvement with olanzapine or risperidone on the Neuropsychiatric Inventory total score, risperidone on the Clinical Global Impression of Changes, olanzapine and risperidone on the Brief Psychiatric Rating Scale (BPRS) hostile suspiciousness factor, and risperidone on the BPRS psychosis factor. There was worsening with olanzapine on the BPRS withdrawn depression factor. Among patients continuing phase 1 treatment at 12 weeks, there were no significant differences between antipsychotics and placebo on cognition, functioning, care needs, or quality of life, except for worsened functioning with olanzapine compared to placebo.Conclusion: In this descriptive analysis of outpatients with Alzheimer's disease in usual care settings, some clinical symptoms improved with atypical antipsychotics. Antipsychotics may be more effective for particular symptoms, such as anger, aggression, and paranoid ideas. They do not appear to improve functioning, care needs, or quality of life. [ABSTRACT FROM AUTHOR]

Background: Second-generation (atypical) antipsychotic drugs are widely used to treat psychosis, aggression, and agitation in patients with Alzheimer's disease, but their benefits are uncertain and concerns about safety have emerged. We assessed the effectiveness of atypical antipsychotic drugs in outpatients with Alzheimer's disease.Methods: In this 42-site, double-blind, placebo-controlled trial, 421 outpatients with Alzheimer's disease and psychosis, aggression, or agitation were randomly assigned to receive olanzapine (mean dose, 5.5 mg per day), quetiapine (mean dose, 56.5 mg per day), risperidone (mean dose, 1.0 mg per day), or placebo. Doses were adjusted as needed, and patients were followed for up to 36 weeks. The main outcomes were the time from initial treatment to the discontinuation of treatment for any reason and the number of patients with at least minimal improvement on the Clinical Global Impression of Change (CGIC) scale at 12 weeks.Results: There were no significant differences among treatments with regard to the time to the discontinuation of treatment for any reason: olanzapine (median, 8.1 weeks), quetiapine (median, 5.3 weeks), risperidone (median, 7.4 weeks), and placebo (median, 8.0 weeks) (P=0.52). The median time to the discontinuation of treatment due to a lack of efficacy favored olanzapine (22.1 weeks) and risperidone (26.7 weeks) as compared with quetiapine (9.1 weeks) and placebo (9.0 weeks) (P=0.002). The time to the discontinuation of treatment due to adverse events or intolerability favored placebo. Overall, 24% of patients who received olanzapine, 16% of patients who received quetiapine, 18% of patients who received risperidone, and 5% of patients who received placebo discontinued their assigned treatment owing to intolerability (P=0.009). No significant differences were noted among the groups with regard to improvement on the CGIC scale. Improvement was observed in 32% of patients assigned to olanzapine, 26% of patients assigned to quetiapine, 29% of patients assigned to risperidone, and 21% of patients assigned to placebo (P=0.22).Conclusions: Adverse effects offset advantages in the efficacy of atypical antipsychotic drugs for the treatment of psychosis, aggression, or agitation in patients with Alzheimer's disease. (ClinicalTrials.gov number, NCT00015548 [ClinicalTrials.gov].). [ABSTRACT FROM AUTHOR]

OBJECTIVES: 'Depression of Alzheimer's Disease' (dAD) is a common complication of Alzheimer's disease and is increasingly recognized as a syndrome with a clinical presentation differing from major depression. Criteria for the diagnosis of dAD have been proposed previously. METHODS: This paper presents these criteria in operationalized format designed to be accessible for clinical use. Four cases are discussed that demonstrate the use of these criteria and illustrate important differences between dAD and major depression. RESULTS: The dAD criteria are broader than DSM-IV criteria for Major Depressive Episode and incorporate caregiver input. CONCLUSIONS: Given the differences between dAD and major depression diagnoses, it is important to assess the efficacy of treatments for dAD. Depression in Alzheimer's Disease-2 (DIADS-2) is a controlled trial of dAD treatments that will also assess the validity of these criteria. [ABSTRACT FROM AUTHOR]

Objective: A consensus conference on the diagnosis and treatment of Alzheimer disease (AD) and related disorders was organized by the American Association for Geriatric Psychiatry, the Alzheimer's Association, and the American Geriatrics Society on January 4 and 5, 1997. The target audience was primary care physicians, and the following questions were addressed: (1) How prevalent is AD and what are its risk factors? What is its impact on society? (2) What are the different forms of dementia and how can they be recognized? (3) What constitutes safe and effective treatment for AD? What are the indications and contraindications for specific treatments? (4) What management strategies are available to the primary care practitioner? (5) What are the available medical specialty and community resources? (6) What are the important policy issues and how can policymakers improve access to care for dementia patients? (7) What are the most promising questions for future research?Participants: Consensus panel members and expert presenters were drawn from psychiatry, neurology, geriatrics, primary care, psychology, nursing, social work, occupational therapy, epidemiology, and public health and policy.Evidence: The expert presenters summarized data from the world scientific literature on the questions posed to the panel.Consensus Process: The panelists listened to the experts' presentations, reviewed their background papers, and then provided responses to the questions based on these materials. The panel chairs prepared the initial drafts of the consensus statement, and these drafts were read by all panelists and edited until consensus was reached.Conclusions: Alzheimer disease is the most common disorder causing cognitive decline in old age and exacts a substantial cost on society. Although the diagnosis of AD is often missed or delayed, it is primarily one of inclusion, not exclusion, and usually can be made using standardized clinical criteria. Most cases can be diagnosed and managed in primary care settings, yet some patients with atypical presentations, severe impairment, or complex comorbidity benefit from specialist referral. Alzheimer disease is progressive and irreversible, but pharmacologic therapies for cognitive impairment and nonpharmacologic and pharmacologic treatments for the behavioral problems associated with dementia can enhance quality of life. Psychotherapeutic intervention with family members is often indicated, as nearly half of all caregivers become depressed. Health care delivery to these patients is fragmented and inadequate, and changes in disease management models are adding stresses to the system. New approaches are needed to ensure patients' access to essential resources, and future research should aim to improve diagnostic and therapeutic effectiveness. [ABSTRACT FROM AUTHOR]

Objective: To reexamine the conclusions of the 1991 National Institutes of Health Consensus Panel on Diagnosis and Treatment of Depression in Late Life in light of current scientific evidence.Participants: Participants included National Institutes of Health staff and experts drawn from the Planning Committee and presenters of the 1991 Consensus Development Conference.Evidence: Participants summarized relevant data from the world scientific literature on the original questions posed for the conference.Process: Participants reviewed the original consensus statement and identified areas for update. The list of issues was circulated to all participants and amended to reflect group agreement. Selected participants prepared first drafts of the consensus update for each issue. All drafts were read by all participants and were amended and edited to reflect group consensus.Conclusions: The review concluded that, although the initial consensus statement still holds, there is important new information in a number of areas. These areas include the onset and course of late-life depression; comorbidity and disability; sex and hormonal issues; newer medications, psychotherapies, and approaches to long-term treatment; impact of depression on health services and health care resource use; late-life depression as a risk factor for suicide; and the importance of the heterogeneous forms of depression. Depression in older people remains a significant public health problem. The burden of unrecognized or inadequately treated depression is substantial. Efficacious treatments are available. Aggressive approaches to recognition, diagnosis, and treatment are warranted to minimize suffering, improve overall functioning and quality of life, and limit inappropriate use of health care resources. [ABSTRACT FROM AUTHOR]

Pieces of the Alzheimer's puzzle are falling into place as new genes are identified and markers detected. But the clinical reality of Alzheimer's disease is still tragedy and hardship for all involved. Your therapeutic role is central--and your help is vital. [ABSTRACT FROM AUTHOR]

Tacrine will be followed by a good number of second-generation cholinesterase inhibitors, some nearing approval. Other promising approaches include anti-inflammatory agents and estrogen -- and the evidence continues to grow. [ABSTRACT FROM AUTHOR]

What are the relative benefits and risks of sertraline and venlafaxine in depressed nursing home residents?METHODSDesign: Randomised controlled trial.Allocation: Unclear.Blinding: Double blind.Follow up period: 10 weeks.Setting: 13 nursing homes, USA; time period not stated.Patients: 52 nursing home residents (mean age 82.5 years) with depression (DSM-IV). Main inclusion criteria: significant dysphoria (Geriatric Depression Scale score .10 and/or. Hamilton Rating Scale for Depression (HAM-D) item 1 rating >2); diagnosis of major depressive episode, minor depression, dementia with. depression, or dysthymic disorder, or 17 item HAM-D score >12; symptom duration >1 month. Exclusions: psychosis; substance abuse; previous mania/schizophrenia; psychotropic drugs in previous 2 weeks; prior adverse reaction or non-response to sertraline or venlafaxine; communication disorders impeding assessment; dangerous weight loss; suicidalily; unstable medical comorbidity; life expectancy <6 months. Participants received placebo for 1 week, those still meeting inclusion but not exclusion criteria were randomised.Intervention: Sertraline (titrated up to maximum of 100 mg/day) or immediate release venlafaxine (titrated up to maximum of 150 mg/day) for 10 weeks.Outcomes: Depressive symptoms (21 item' HAM-D score), adverse events.Patient follow up: 90%.MAIN RESULTSAt 10 weeks, there were no significant differences in improvement of symptoms between groups (mean improvement in HAM-D score: 8 with sertraline v 4.6 with venlafaxine; p = 0.069; intention to treat analysis). Sertraline was associated with significantly fewer withdrawals due to serious adverse events or side effects than venlafaxine (5/25 (20%) with sertraline v 12/27 (44%) with venlafaxine; Fisher's exact p = 0.019).CONCLUSIONSThere was no evidence for immediate release venlafaxine having greater efficacy than sertraline in depressed nursing home residents. This result may have been because the study was underpowered to detect a difference. However, venlafaxine was less well tolerated than sertraline in this population. [ABSTRACT FROM AUTHOR]

The cognitive reserve (CR) hypothesis posits that individuals can differ in how their brain function is disrupted by pathology associated with aging and neurodegeneration. Here, we test this hypothesis in the continuum from cognitively normal to at-risk stages for Alzheimer's Disease (AD) to AD dementia using longitudinal data from 490 participants of the DELCODE multicentric observational study. Brain function is measured using task fMRI of visual memory encoding. Using a multivariate moderation analysis, we identify a CR-related activity pattern underlying successful memory encoding that moderates the detrimental effect of AD pathological load on cognitive performance. CR is mainly represented by a more pronounced expression of the task-active network encompassing deactivation of the default mode network (DMN) and activation of inferior temporal regions including the fusiform gyrus. We devise personalized fMRI-based CR scores that moderate the impact of AD pathology on cognitive performance and are positively associated with years of education. Furthermore, higher CR scores attenuate the effect of AD pathology on cognitive decline over time. Our findings primarily provide evidence for the maintenance of core cognitive circuits including the DMN as the neural basis of CR. Individual brain activity levels of these areas during memory encoding have prognostic value for future cognitive decline., Competing Interests: Competing interests The authors declare the following competing interests: Y.S. consults for Eisai, Lilly, and Arcadia. Columbia University licenses the Dependence Scale, and in accordance with university policy, Y.S. is entitled to royalties through this license. B.H.S. is involved in clinical studies by Roche, Biogen, and Hummingbird Diagnostics, but does not receive personal funds from any of them. S.T. is member of the DSMB of the study ENVISION (Biogen). J.W. acted as a consultant for Immungenetics, Noselab, and Roboscreen. J.W. further served on a scientific advisory board for Abbott, Biogen, Boehringer Ingelheim, Lilly, Immungenetics, MSD Sharp-Dohme, Noselab, Roboscreen, and Roche. J.W. received honoraria for presentations from Beijing Yibai Science and Technology Ltd, Eisai, Gloryren, Janssen, Pfizer, Med Update GmbH, Roche, and Lilly. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Background and Objectives: CSF biomarkers have immense diagnostic and prognostic potential for Alzheimer disease (AD). However, AD is still diagnosed relatively late in the disease process, sometimes even years after the initial manifestation of cognitive symptoms. Thus, further identification of biomarkers is required to detect related pathology in the preclinical stage and predict cognitive decline. Our study aimed to assess the association of neurogranin and β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) with cognitive decline in individuals with subjective cognitive decline (SCD)., Methods: We enrolled participants with available neurogranin and BACE1 measurements in CSF from the DELCODE (DZNE-Longitudinal Cognitive Impairment and Dementia, Germany) cohort. The longitudinal change of Preclinical Alzheimer's Cognitive Composite score was assessed as the primary outcome in participants with SCD and controls. The secondary outcome was defined as conversion of SCD to mild cognitive impairment (MCI) during follow-up. Levels of neurogranin, BACE1, and neurogranin/BACE1 ratio across groups were compared by analysis of covariance after adjustment for demographics. The linear mixed-effects model and Cox regression analysis were applied to evaluate their association with cognitive decline and progression of SCD to MCI, respectively., Results: A total of 530 participants (mean age: 70.76 ± 6.01 years, 48.7% female) were analyzed in the study. The rate of cognitive decline was faster in individuals with SCD with higher neurogranin and neurogranin/BACE1 ratio (β = -0.138, SE = 0.065, p = 0.037, and β = -0.293, SE = 0.115, p = 0.013). Higher baseline neurogranin and neurogranin/BACE1 ratio were associated with an increased rate of conversion from SCD to MCI (hazard ratio [HR] 1.35 per SD, 95% CI 1.03-1.77, p = 0.028, and HR 1.53 per SD, 95% CI 1.13-2.07, p = 0.007). In addition, the impact of higher neurogranin levels on accelerating the rate of cognitive decline was more pronounced in the SCD group than in cognitively unimpaired controls (β = -0.077, SE = 0.033, p = 0.020)., Discussion: Our findings suggest that CSF neurogranin and BACE1 begin to change in the preclinical stage of AD and they are associated with clinical progression in individuals with SCD.

Cone-beam computed tomography (CBCT) systems, with their flexibility, present a promising avenue for direct point-of-care medical imaging, particularly in critical scenarios such as acute stroke assessment. However, the integration of CBCT into clinical workflows faces challenges, primarily linked to long scan duration resulting in patient motion during scanning and leading to image quality degradation in the reconstructed volumes. This paper introduces a novel approach to CBCT motion estimation using a gradient-based optimization algorithm, which leverages generalized derivatives of the backprojection operator for cone-beam CT geometries. Building on that, a fully differentiable target function is formulated which grades the quality of the current motion estimate in reconstruction space. We drastically accelerate motion estimation yielding a 19-fold speed-up compared to existing methods. Additionally, we investigate the architecture of networks used for quality metric regression and propose predicting voxel-wise quality maps, favoring autoencoder-like architectures over contracting ones. This modification improves gradient flow, leading to more accurate motion estimation. The presented method is evaluated through realistic experiments on head anatomy. It achieves a reduction in reprojection error from an initial average of 3 mm to 0.61 mm after motion compensation and consistently demonstrates superior performance compared to existing approaches. The analytic Jacobian for the backprojection operation, which is at the core of the proposed method, is made publicly available. In summary, this paper contributes to the advancement of CBCT integration into clinical workflows by proposing a robust motion estimation approach that enhances efficiency and accuracy, addressing critical challenges in time-sensitive scenarios.

Background: Multiple system atrophy (MSA), an atypical parkinsonian syndrome, is a rapidly progressive neurodegenerative disease with currently no established fluid biomarkers available. MSA is characterized by an oligodendroglial α-synucleinopathy, progressive neuronal cell loss and concomitant astrocytosis. Here, we investigate glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) as fluid biomarkers for differential diagnosis, assessment of clinical disease severity and prediction of disease progression in MSA., Methods: GFAP and NfL levels were analyzed in plasma and CSF samples of 47 MSA patients as well as 24 Parkinson's disease (PD) and 25 healthy controls (HC) as reference cohorts. In MSA, biomarker levels were correlated to baseline and longitudinal clinical disease severity (UMSARS scores)., Results: In MSA, GFAP levels in CSF and plasma predicted baseline clinical disease severity as indicated by UMSARS scores, while NfL levels predicted clinical disease progression as indicated by longitudinal changes in UMSARS scores. Cross-sectionally, NfL levels in CSF and plasma were significantly elevated in MSA compared to both PD and HC. Receiver operating curves (ROC) indicated high diagnostic accuracy of NfL for distinguishing MSA from PD (CSF: AUC = 0.97, 95% CI 0.90-1.00; plasma: AUC = 0.90, 95% CI 0.81-1.00)., Discussion: In MSA, GFAP shows promise as novel biomarker for assessing current clinical disease severity, while NfL might serve as biomarker for prediction of disease progression and differential diagnosis of MSA against PD., (© 2024. The Author(s).)

Accumulation of pathological tau isoforms, especially hyperphosphorylated tau at serine 396 (pS396-tau) and tau oligomers, has been demonstrated in the retinas of patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Previous studies have noted a decrease in retinal ganglion cells (RGCs) in AD patients, but the presence and impact of pathological tau isoforms in RGCs and RGC integrity, particularly in early AD stages, have not been explored. To investigate this, we examined retinal superior temporal cross-sections from 25 patients with MCI (due to AD) or AD dementia and 16 cognitively normal (CN) controls, matched for age and gender. We utilized the RGC marker ribonucleic acid binding protein with multiple splicing (RBPMS) and Nissl staining to assess neuronal density in the ganglion cell layer (GCL). Our study found that hypertrophic RGCs containing pS396-tau and T22-positive tau oligomers were more frequently observed in MCI and AD patients compared to CN subjects. Quantitative analyses indicated a decline in RGC integrity, with 46-55% and 55-56% reductions of RBPMS + RGCs (P<0.01) and Nissl + GCL neurons (P<0.01-0.001), respectively, in MCI and AD patients. This decrease in RGC count was accompanied by increases in necroptotic-like morphology and the cleaved caspase-3 apoptotic marker in RGCs of AD patients. Furthermore, there was a 2.1 to 3.1-fold increase (P<0.05-0.0001) in pS396-tau-laden RGCs in MCI and AD patients, with a greater abundance observed in individuals with higher Braak stages (V-VI), more severe clinical dementia ratings (CDR=3), and lower mini-mental state examination (MMSE) scores. Strong correlations were noted between the decline in RGCs and the total amount of retinal pS396-tau and pS396-tau + RGCs, with pS396-tau + RGC counts correlating significantly with brain neurofibrillary tangle scores ( r = 0.71, P= 0.0001), Braak stage ( r = 0.65, P= 0.0009), and MMSE scores ( r = -0.76, P= 0.0004). These findings suggest that retinal tauopathy, characterized by pS396-tau and oligomeric tau in hypertrophic RGCs, is associated with and may contribute to RGC degeneration in AD. Future research should validate these findings in larger cohorts and explore noninvasive retinal imaging techniques that target tau pathology in RGCs to improve AD detection and monitor disease progression., Competing Interests: Competing interest: The authors declare no conflict of interest relevant for this study.